Peri-exposure prophylaxis is a potentially effective method of protecting targeted populations at high risk of exposure during a natural or intentional outbreak of Ebola virus. Preclinical murine data presented in this proposal indicates that poly-ICLC could provide such protection with a high safety margin in an epidemic containment situation. Poly-ICLC (Hiltonol(TM)) is a stabilized, clinically safe and active, yet relatively simple dsRNA viral-mimic whose broad activation of both innate and adaptive host immune responses results in an immediate non-specific antiviral state in the context of stimulation of longer-term specific humoral and cellular immunity. Its demonstrated broad antiviral protection when delivered either intramuscularly or intranasally make it a potentially valuable agent for inclusion in the Nation's biodefense armamentarium. General Aims: To accelerate the development of the dsRNA viral-mimic poly-ICLC (Hiltonol(TM)) as a safe, effective and logistically simple prophylaxis and early treatment for ebola virus infection in humans. Specific Aims: A) To determine the optimal dose and schedule of poly-ICLC for prophylaxis and treatment of Ebola virus infection in an established murine challenge model, and to further elucidate its mechanism of action and effect on viral load and on elements of innate and adaptive immunity B) To confirm the safety and efficacy of poly-ICLC in prophylaxis and treatment of ebola virus infection in a well-established non-human primate (cynomolgous) challenge model, utilizing the optimal dose schedules determined in the murine studies. C) To develop GMP manufacturing methods for Poly-ICLC, in compliance with specific FDA guidance.